The Activin Social Network: Activin, Inhibin and Follistatin in Breast Development and Cancer.

Activins and inhibins are closely related protein heterodimers with similar tissue distribution, yet these two complexes have opposing functions in development and disease. Both are secreted cytokine hormones, with activin being the primary inducer of downstream signaling cascades and inhibin acting as a rheostat that exquisitely governs activin function. Adding to the complexity of activin signaling, follistatin, a high glycosylated monomeric protein, binds activin with high affinity, also restraining downstream pathway activation but through a mechanism distinct from that of inhibin. These three proteins were first identified as key ovarian hormones in the pituitary-gonadal axis that direct synthesis and secretion of follicle-stimulating hormone from the pituitary, hence controlling folliculogenesis. Research over the last thirty years has expanded the roles of these proteins, first by discovering the ubiquitous expression of the trio and then implicating them in a wide array of biological functions. In concert, these three hormones govern tissue development, homeostasis, and disease in multiple organ systems through diverse autocrine and paracrine mechanisms. Herein, we review the actions of activin and its biological inhibitors, inhibin and follistatin, in mammary gland morphogenesis and cancer.